6. Pathogenesis of asthma 1 Flashcards
1
Q
What is asthma?
A
- A chronic inflammatory disease of the lung.
- It is common and affects around 300 million people worldwide.
- Around 250,000 asthma-related death annually.
2
Q
What does asthma cause?
A
- Cells of the immune system act with epithelial cells cause tissue damage.
- Bronchial hyper reactivity (BHR)
- Mucus overproduction
- Airway wall remodelling
- Airway narrowing.
3
Q
What are the common symptoms of asthma?
A
Repeated episode of wheezing, shortness of breath and chest tightness.
4
Q
How are histological changes in the asthmatic lung studied?
A
- Tissue section of the medium airway.
- Stain the tissue with Movat’s pentachrome.
5
Q
What histological changes occur in the asthmatic airway?
A
- Hyperplasia of the epithelium
- Hypersecretion of mucus
- Thickening of the basement membrane
- Increased smooth muscle volume
6
Q
What do all the histological changes in the asthmatic airway cause?
A
- They cause significant narrowing of the airway.
- This compromises lung function.
7
Q
What are the 2 traditional types of asthma?
A
- Allergic asthma
- Non-allergic asthma
8
Q
What is allergic asthma?
A
- The more prevalent type of asthma.
- 50% of adult asthma is allergic asthma.
- the majority of childhood asthma is allergic asthma.
- There must be an IgE allergic reaction to an aero-antigen or another antigen that drives asthma.
9
Q
What is non-allergic asthma?
A
- It is mostly found in adults
- There no presence of IgE.
10
Q
Why was the classification of asthma reconsidered?
A
Due to its heterogeneity.
11
Q
What factors are considered in the way of classifying asthma now?
A
- Clinical presentation
- Age of onset
- Genetic susceptibility
- Response to environmental factors
- Degree of inflammation/BHR
- Degree of tissue remodelling
- Response to therapy
- Prognosis
12
Q
What is the prevalence of asthma in the UK?
A
- Used data from 2007
- Samples were taken from the same place and with the same method to rule out confounding factors.
- Asthma prevalence has increased over time in the UK.
- Diagnosis of asthma has reached a plateau.
- Currently it is estimated that over 12% of the population in the UK has been diagnosed with asthma.
13
Q
What causes asthma?
A
- Host genetic risk factors
- Environmental risk factors including susceptibility and precipitating factors.
- There is complex interplay between these factors that decides the development and severity of asthma.
14
Q
What is the genetic heritability rate of asthma?
A
35-95%
15
Q
What are susceptibility environmental risk factors in asthma?
A
- These are things that act on the genetic predisposition to asthma to turn you from a healthy person to an asthmatic person.
- They act on the genetic risk.
16
Q
What are precipitating environmental risk factors in asthma?
A
These are things that will set off an asthma attack.
17
Q
What kind of inheritance does asthma show?
A
- 1 or 2 parents with asthma or another allergic disease increases risk.
- No 1 mutation causes asthma
- Asthma is polygenic so lots of genes contribute to the overall susceptibility profile of a person.
18
Q
What are the asthma susceptibility loci?
A
- Gene expressed in the airway
- Genes that regulate CD4 Th2, ILC2 and type 2 immune responses.
- Other genes
19
Q
What genes expressed in the airway can effect asthma susceptibility?
A
- Chemokines like CCL5
- Antimicrobial peptides like DEFB1
- Epithelial barrier protein like FLG
20
Q
What genes that regulate Th2 CD4 T cells and other type 2 responses can effect asthma susceptibility?
A
- Transcription factors like GATA3, RORa and STAT3.
- Cytokines: IL4, IL5, IL10, IL13 and IL33
- Cytokine receptors like IL4R and IL5R
21
Q
What genes that regulate other functions can effect asthma susceptibility?
A
- Proteinase or proteinase inhibitors like ADAM33
- Signalling proteins like Notch4 and SMAD3
22
Q
What can we gain an idea of by looking at the asthma susceptibility loci?
A
We can start to build up an idea of the pathogenesis of asthma.
23
Q
Examples of environmental risk factors - susceptibility
A
- Indoor and outdoor allergens
- Occupational sensitisers like solvents
- Tobacco smoke (active or passive)
- Air pollutants
- Respiratory infections (mostly viral)
- Parasitic infections
- Family size
- Diet and drugs
- Obesity
24
Q
Examples of environmental risk factors - Precipitating
A
- Overlaps with susceptibility list.
- Indoor and outdoor allergens.
- Air pollutants
- Tobacco smoke (active or passive)
- Exercise and hyperventilation
- Respiratory infections (mostly viral)
- Weather changes like thunderstorms
- Sulphur dioxide (a common preservative)
- Extreme emotional expression
25
Q
Is asthma a condition of affluent societies?
A
- More affluent countries have more urbanisation and industrialisation.
- This increases pollution and exposure to indoor allergens.
- A large scale international collaboration from 1998.
- 463,801 children studied across 56 countries.
- Show asthma is more of a problem for more western societies.
- There are some contradictions.
26
Q
Why is the global spread of asthma a complex picture?
A
Because it is a complex multigenic and multifactorial disease
27
Q
What is the hygiene hypothesis?
A
- It was originally proposed in 1989 by David Strachan.
- He studied hay fever prevalence in 17,000 British children.
- Found hay fever prevalence is inversely related to the number of children in the household.
- He hypothesised that allergic diseases could be prevented by an infection transmitted by unhygienic contact with older siblings. family size has decreased over time and higher standards of personal cleanliness have resulted in reduced opportunity for infections. This could increase allergic disease.
- It was not well received at 1st as it was know some infections trigger asthma.
- It became more accepted when Th1 and Th2 cells were discovered.
28
Q
What balance is needed between Th1 and Th2 cells to maintain immune balance?
A
- Th1 and Th2 cells exist in a balance.
- They are mutually antagonistic to each other.
- Th1 cells arise in response to bacterial and viral infections and inhibit Th2 response.
- Th2 cells drive IgE and allergy and inhibit Th1 cells.
29
Q
What can happen if the balance between Th1 and Th2 cells is disrupted?
A
- If you don’t have a lot of infections and a strong Th1 response, the inhibition of Th2 by Th1 doesn’t occur.
- This can dysregulate the Th2 response and cause allergic disease.
- This supports the hygiene hypothesis
30
Q
What is the Von Mutius’ Westernisation hypothesis?
A
- This is related to the hygiene hypothesis.
- It was proposed by allergist Erika van Mutius in 1994.
- She studied asthma and allergy in children in east and west Germany.
- This studied the environmental impact of allergy on a group of ethnically similar group of children.
- It showed significantly more asthma and hay fever in children from West Germany.
31
Q
What did the Von Mutius’ Westernisation hypothesis find?
A
- Significantly more asthma and hay fever in children from west Germany.
- East Germany was poorer, less developed, more polluted and had more bronchitis.
- Children from west Germany were sensitised to aeroallergens derived from mites, cates and pollen significantly more.
32
Q
How are dust mites a precipitating environmental risk factor?
A
- They are a source of indoor antigens.
- These are important in developing asthma and triggering asthma attacks.
- Allergens called Derp1 and Derp9
33
Q
What is the Platts-Mills’ Obesity hypothesis?
A
- It states that other factors related to the western lifestyle that need to be considered in the development of asthma.
- “Increased time exposed to indoor allergens, over eating and decreased physical activity”
- Children has less physical activity and are exposed more to dust mites in warm houses.
- They have less physical activity which can increase non-specific bronchial reactivity.
- This can help explain the areas that don’t fit into the hygiene hypothesis.
34
Q
What is the microflora hypothesis?
A
- A Westernised lifestyle can cause dramatic changes in the gut microflora.
- It is not known if it actively drives asthma or if changing patterns of commensal activity changes the immune response due to changing immune regulatory interactions between commensal and the immune system.
- There is a positive correlation between antibiotic use and risk for asthma/allergy.
- Correlation between altered faecal microbiota composition and atopy.
- Successful suppression of allergy by alterations in diet/probiotics.
- Dysbiosis increases risk of asthma in later life
35
Q
What evidence from mice supports that microflora hypothesis?
A
- Germ-free mice have various defects in immune response generation.
- Antibiotic treatment can promote Th2 responses
- Probiotics can reduce airway allergic responses.
36
Q
How does the gut flora influence lung immunology?
A
- Both the lungs and gut are mucosal surfaces which are home to trillions of microbes.
- Most inhaled micro-particles stick to mucus in the nasopharynx and upper airways. This is then swallowed and exposed to the immune cells in the gut.
- Several mechanisms, including microbiota influences, contribute to the maintenance of mucosal tolerance, preventing damaging immune responses.
- Changes in the gut flora perturb the normal mucosal tolerance mechanisms which can cause hyperreactivity to harmless antigens.
- A balanced microbiota helps to maintain mucosal tolerance to allergens, which prevents asthma.
37
Q
How does the environment children grow up in alter asthma susceptibility?
A
- There was a study done in Finland and Germany characterising home dust microbiota. Comparing urban and farm environments.
- Rural farms have a rich home dust microbiota which shapes lung immunity and reduces the risk of asthma.
- Asthma risk decreases for urban children the more similar their home microbiota composition is to a farm home microbiota.
- Alterations in select bacterial species likely have a protective effect.
- Could we identify which bacteria are protective and tweak them to use as a therapeutic?
38
Q
What is the epithelial barrier hypothesis?
A
- It links the ideas of the microflora and hygiene hypothesis.
- It was shown that epithelial barrier integrity problems were linked to IBD, allergy and asthma.
- The epithelial barrier is more likely to be exposed to damaging agents in a westernised society.
- These include toxins, enzymes, emulsifiers, pollution and processed food.
- This leads to the colonisation of opportunistic pathogens.
39
Q
What is the cycle of the epithelial barrier hypothesis?
A
- Exposure to barrier damaging agents
- Inflammation in the epithelium and barrier damage.
- Colonisation of opportunistic pathogens
- Microbial dysbiosis and decreased biodiversity.
- Translocation of microbiota to subepithelial layers.
- Immune response to commensals and opportunistic pathogens which causes further damage to the epithelial barrier
- Defective healing capacity of the epithelium.
- More exposure to barrier damaging agents etc.
40
Q
Why is climate change linked to increased asthma levels?
A
- Increased pollen levels cause increased allergic asthma.
- Increased pollen is due to increased temperature, CO2 and longer pollen seasons with higher pollen loads. This contributes to the induction of asthma.
- Thunderstorms can increase severe asthma attacks due to increased humidity and rupturing aero antigens to release smaller antigens.
- Wildfires and sandstorms also release more aero antigens.
- Heat waves stress the immune system
- Collectively these change the exposome and lead to immune dysregulation causing more asthma and other immune diseases like cancer.
41
Q
What cells mediate allergic asthma?
A
Th2 cells
42
Q
What evidence shows allergic asthma is Th2 mediated?
A
- In allergic asthma there are increased number of CD4+ T cells producing IL-4 and IL-5.
- There are eosinophils in the respiratory tract fluid and bronchial biopsies which IL-5 recruits.
- There is serum IgE present which is a product of IL-4 driven class switching.
- Unsupervised clustering algorithms reveal Th2hi and Th2lo subtypes which group patients based on the presence of IL4/5/13 and IgE.
43
Q
How do you make an animal model of allergic asthma?
A
- Mice don’t develop asthma so you have to induce it.
- The mice are sensitised with the model antigen OVA and some adjuvants.
- The mouse is then challenged with intranasal aerosolised OVA.
- This triggers asthma-like airway inflammation with eosinophilic inflammation, Th2 cytokines and airway hyperresponsiveness.
44
Q
How do asthma-like animal models provide evidence for asthma as a Th2 disorder?
A
- If you deplete CD4+ T cells in this model it abolishes key features of asthma.
- If you transfer the OVA-specific Th2 cells into another mouse it will develop asthma.
- If you transfer Th1 cells or IL-12 into an asthma mouse, it suppresses asthma.
- IL-4, IL-5 and IL-13 deficient mice have substantially fewer features of asthma in the OVA model.
- Epigenetic changes occur in CD4+ T cells which inhibit Th1 cytokine production and promote Th2 cytokines production.
45
Q
What does sensitisation to allergens cause?
A
- It establishes the underlying immune response to asthma.
- It is caused by low levels of aerosolised antigens.
- The most clinically relevant allergens are enzymes that interfere with physiological systems.
46
Q
What are Derp1 and Derp9?
A
- The major house dust mite allergens.
- They have serine and cysteine protease activity.
- They cleave tight junction occludin proteins.
- This increases epithelial permeability, which increases access to immune cells like dendritic cells, which induce a Th2 response.
- They can also cleave CD23 off B cells to cause an up-regulation of IgE synthesis.
47
Q
What is CD23?
A
The low affinity IgE receptor on B cells - FceRII
48
Q
How do dendritic cells drive Th2 responses?
A
- Dendritic cells sample antigens in the airway lumen or they can catch antigens that have crossed the epithelial barrier.
- DC are activated by endogenous and exogenous alarmins which can be released by activate/damaged epithelial cells.
- These alarmin cytokines include IL-33, IL-25 and TSLP.
- These epithelial derived cytokines drive DC maturation and condition the DC to induce a type 2 response.
- DC migrate to the lymph node, present the antigen to naive CD4+ T cells and drive Th2 cell differentiation.
49
Q
What have mouse models shown about the role of dendritic cells in asthma?
A
- Mouse models show DC are necessary for the induction of Th2 responses during sensitisation.
- Depletion of DC in sensitised mice during allergen challenge can suppress many features of asthma.
- DC recruit effector T cells to the site of inflammation in the lungs by the production of chemokines and form clusters in the airways and blood vessels.
- Numbers of activated DC increase in the airways of asthmatics
- Polymorphisms at HLA-DRB1 and HLA-DQA1 locus are associated with asthma.
- DC produce chemokines and cytokines that activate other immune cells that perpetuate inflammation
50
Q
What is the mechanism of sensitisation in asthma using Derp1 as an example?
A
- Derp1 is the allergen and its cleaves occludin in the tight junctions.
- The dendritic cell detects the allergen and takes it to the lymph node for antigen presentation.
- The dendritic cells preferentially induces Th2 responses.
- Th2 cells produce cytokines that drive B cells to produce IgE (IL-4).
- Plasma B cells then move back the mucosa in the lungs and produce IgE.
- The IgE binds to the FceR1 receptor on mast cells and coat them.
- This person is now sensitised to Derp1.
51
Q
What happens on allergen re-exposure in asthma using Derp1 as an example?
A
- When Derp1 is encountered again is binds to the IgE on mast cells.
- It cross links the IgE.
- This triggers degranulation of the mast cells and causes the asthmatic symptoms.
52
Q
How are Mast cells activated following allergen exposure?
A
- IgE binds to the FceR1 on the mast cells without an antigen.
- It activates when the antigen binds to multiple IgE on the mast cells surface at the same time. This is crosslinking.
- This causes degranulation.
53
Q
What is the role of mast cells in the acute asthma response?
A
- Mast cells are maintained in the airway by IL-9.
- They are rapidly activated by IgE crosslinking.
- Even low levels of antigen can trigger degranulation.
- Degranulation releases pre-formed inflammatory mediators into the tissue.
- Histamine is released which acts on blood vessels to increase blood flow and vascular permeability.
- Proteases activate matrix metalloproteases to cause tissue damage
54
Q
What is released from mast cell granulates and what do they do?
A
- Prostaglandins and leukotrienes which increase vascular permeability, smooth muscle contraction and mucus production.
- Platelet activating factor.
- Cytokines (IL-4/IL-13) and chemokines which recruit and influence other immune cells to drive further inflammation.
55
Q
What is the immediate phase response in asthma?
A
- Exposed to antigen
- Lungs function massively decreases within about 30 mins.
- Due to mast cells inducing narrowing of the airway due to bronchial smooth muscle contraction.
- Immediate hypersensitivity reaction
56
Q
What is the late phase response in asthma?
A
- It depends on the allergen dose and the severity of response to trigger it.
- It occurs 6-8 hours after allergen exposure.
- Slow drop off in lung function
- Not caused by mast cells but a different type of immune response.
57
Q
How is lung function measured in asthmatics?
A
Peak expiratory flow rate
58
Q
How is the late phase response in asthma induced?
A
- It is dependent on the allergen dose.
- There is continued synthesis of inflammatory mediators by mast cells, which perpetuates inflammation in the lungs.
- VEGF causes vasodilation and vascular leakage causing oedema.
- Cytokines and chemokines secreted mostly by mast cells activate and recruit other immune cells.
- Recruitment of eosinophils and Th2 cells.
59
Q
How are eosinophils recruited in asthma?
A
- Normally only very small number of eosinophils are found in circulation as they are very dangerous.
- Eosinophils accumulate in the asthmatic airways.
- Th2 cells produce IL-5 which triggers eosinophil production and release from the bone marrow into circulation.
- IL-4 and IL-13 act on endothelial cells and fibroblast to secrete eotaxins.
- eotaxins recruit eosinohils from the blood to sites of inflammation.
- Eotaxins include CCL11, CCL24 and CCL26 which binds to CCR3.
- Th2 cells also express CCR3 so they are also recruited by eotaxins.
60
Q
How do eosinophils and Th2 cells exit the blood vessels?
A
- Histamine and leukotrienes released by mast cells in the acute response increase the expression of P-selectin and E-selectin on the endothelium.
- These initiate leukocyte rolling to slow down the cells.
- IL-13 increases ICAM1 and VCAM1 expression of the airway endothelium. These are adhesion molecules.
- These interact with integrins on leukocytes to arrest their movement.
- the cells them migrated out of the blood vessel and into the inflamed lung tissue.
61
Q
What is diapedesis?
A
The passage of cells through the blood vessel wall.
62
Q
How do eosinophils contribute to the pathogenesis of asthma?
A
- Major basic protein is the major constituent of the eosinophil granule.
- MBP is really good for getting rid of parasites like helminths but is very toxic to host cells.
- This damage triggers mast cell and basophil degranulation.
- This causes epithelial damage and opening of tight junctions which increases vascular permeability, oedema and mucus production.
- Major basic protein disrupts the epithelium so more antigen is exposed perpetuating the inflammatory response to that antigen.
63
Q
How do Th2 derived cytokines contribute to allergic asthma pathology?
A
- Dendritic cells aid the differentiation to Th2 cells which produce type 2 cytokines.
- IL-5 drive eosinophilia.
- IL-4 drive production of IgE from B cells.
- IL-4 and IL-13 allows cells to move from the blood to inflamed tissues easily.
- IL-13 drives goblet cells metaplasia and bronchial hyper reactivity.
64
Q
How do epithelial cytokines contribute to asthma pathology?
A
- They act as alarmins to condition dendritic cells to make Th2 cells.
- These include IL-33, IL-25 and TSLP.
- Some parts of the farm dust microbiome inhibits some of these pathways and down regulated inflammation.
65
Q
What does multiple asthma attacks over time lead to?
A
Fibrosis and permanent damage to the lungs.
66
Q
Could altering the lung microbiome treat or prevent asthma?
A
- The use of pre and probiotics are being looked at to help build a healthy microbial community in the lungs as evidence suggest this can aid the development of tolerance.
- 1 study has suggested that pre and probiotics use helps reduce the systemic production of Th2 cytokines in allergic asthma.
- Combine nutritional additions like fish oils with probiotics showed improvement of pulmonary function and reduced the requirement for short acting inhaled bronchodilators
- However this does need further investigation.
67
Q
Can the microbiome impact a patient’s response to asthma treatment?
A
- Yes
- Differences in composition has been shown to impact treatment efficacy or the severity of side effects.
- This needs to be explored further to see how it impacts asthma specifically.
